ABSTRACT
This trial was conducted to evaluate the pharmacokinetics and safety of a sodium oxybate (gamma-hydroxybutyrate [GHB]) oral solution in narcoleptic patients after acute and chronic treatment. An open-label, two-period, two-treatment study design was used. Trial subjects included 13 patients with polysomnographically confirmed narcolepsy. The patients were administered a bedtime dose of 4.5 g of sodium oxybate while in a sleep research center. They were subsequently treated with sodium oxybate at the nightly dose of 4.5 g for 8 weeks. The patients then returned to the sleep center and were again treated with the 4.5-g sodium oxybate dose at bedtime. Blood samples (5 mL) were collected at 18 time points before and up to 7 hours after both the first dose of sodium oxybate and following 8 weeks of dosing. Plasma samples were analyzed for oxybate content by a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Noncompartmental methods were applied in the determination of pharmacokinetic parameters from each patient's plasma oxybate concentration versus time curve. No serious adverse events were recorded, and all patients completed the study. Headache, enuresis, and leg cramps were reported as adverse experiences. With both acute and chronic dosing, sodium oxybate was rapidly absorbed and eliminated with an apparent half-life of about 40 minutes. The only changes observed in the kinetics of oxybate after 8 weeks of treatment were a 13% and 16% increase in peak concentration (C(max)) and systemic exposure (AUC), respectively. The pharmacokinetics of sodium oxybate in narcoleptic patients were not changed in any clinically significant manner when the drug was chronically administered. The drug was well tolerated.
Subject(s)
Central Nervous System Depressants/pharmacokinetics , Narcolepsy/drug therapy , Sodium Oxybate/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Central Nervous System Depressants/administration & dosage , Central Nervous System Depressants/blood , Drug Administration Schedule , Female , Half-Life , Humans , Male , Metabolic Clearance Rate , Middle Aged , Narcolepsy/metabolism , Pharmaceutical Solutions , Sodium Oxybate/administration & dosage , Sodium Oxybate/blood , Time FactorsABSTRACT
Sodium oxybate (Xyrem; gamma-hydroxybutyrate) oral solution was recently approved in the United States for the treatment of cataplexy in patients with narcolepsy. Two single-center, randomized, open-label studies in healthy volunteers receiving single oral 4.5-g doses of sodium oxybate evaluated effects of (1) gender on oxybate pharmacokinetics and (2) food on its oral bioavailability. In the latter study, one dose was administered after an overnight fast, another after a high-fat meal; 1 week separated treatments. Sodium oxybate pharmacokinetics was not significantly different between sexes. However, food significantly altered the bioavailability of oxybate by decreasing mean peak plasma concentration, increasing median time-to-peak concentration, and decreasing the area under the plasma concentration-time curve. Food did not affect elimination and urinary excretion of unchanged drug. No dose adjustment of sodium oxybate based on sex is indicated. Although significant food effects were observed, these are minimized in patients by the nocturnal dosing of sodium oxybate hours after the evening meal at a consistent time interval following food ingestion.
